Gut Microbe-Derived Lipids Shape Chronic Inflammation in Cardiometabolic Disease

ABSTRACTRecent evidence has emerged that microbes resident in the human intestine represent a keytransmissible environmental factor contributing to a number of human diseases including obesitydiabetes atherosclerotic cardiovascular disease. However mechanisms by which gut microbial-derived factors signal to the host to promote these common cardiometabolic diseases are largelyunknown. Here we have discovered that the circulating level of select gut microbe-derived lipidscalled N-acyl amides are markedly reduced in the circulation of humans with obesity-driven heartfailure. We also show that gut bacterially-derived N-acyl amides can signal through the host Gprotein-coupled receptor GPR119 to reorganize inflammatory and metabolic pathways in the host.To follow up here we propose the following central hypothesis: The microbial metabolite N-oleoylserinol is a meal-related lipokine that signals via the host receptor GPR119 to suppressmetainflammation in cardiometabolic disease. To test this we have created several innovativemethods to increase circulating levels of bacterially-derived N-acyl amides and will now leveragethese in preclinical mouse models of obesity diabetes and atherosclerosis. Successfulcompletion of this project will advance the concept that metaorganismal endocrinology (i.e.microbial metabolite host receptor crosstalk) can impact obesity and atherosclerosis and willdemonstrate that the host N-acyl amide receptor GRP119 may hold untapped therapeuticpotential in cardiometabolic disease.